Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:B6E4X6 (mutant p53)
 3,342 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

MDM2 is a critical negative regulator of the p53 tumor suppressor protein. Recently, small-molecule antagonists of MDM2, the Nutlins, have been developed to inhibit the p53-MDM2 interaction and activate p53 signaling. However, half of human cancers have mutated p53 and they are resistant to Nutlin treatment. Here, we report that treatment of the p53-mutant malignant peripheral nerve sheath (MPNST) and p53-null HCT116 cells with cisplatin (Cis) and Nutlin-3a induced a degree of apoptosis that was significantly greater than either drug alone. Nutlin-3a also increased the cytotoxicity of both carboplatin and doxorubicin in a series of p53-mutant human tumor cell lines. In the human dedifferentiated liposarcoma cell line (LS141) and the p53 wild-type HCT116 cells, Nutlin-3a induced downregulation of E2F1 and this effect appeared to be proteasome dependent. In contrast, in MPNST and HCTp53-/- cells, Nutlin-3a inhibited the binding of E2F1 to MDM2 and induced transcriptional activation of free E2F1 in the presence of Cis-induced DNA damage. Downregulation of E2F1 by small interfering RNA significantly decreased the level of apoptosis induced by Cis and Nutlin-3a treatment. Moreover, expression of a dominant-negative form of E2F1 rescued cells from apoptosis, whereas cells overexpressing wild-type E2F1 showed an increase in cell death. This correlated with the induction of the proapoptotic proteins p73alpha and Noxa, which are both regulated by E2F1. These results indicate that antagonism of MDM2 by Nutlin-3a in cells with mutant p53 enhances chemosensitivity in an E2F1-dependent manner. Nutlin-3a therefore may provide a therapeutic benefit in tumors with mutant p53 provided it is combined with chemotherapy.
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PMID:Mouse double minute antagonist Nutlin-3a enhances chemotherapy-induced apoptosis in cancer cells with mutant p53 by activating E2F1. 1714 34

Wild-type p53 is a conformationally labile protein that undergoes nuclear-cytoplasmic shuttling. MDM2-mediated ubiquitination promotes p53 nuclear export by exposing or activating a nuclear export signal (NES) in the C terminus of p53. We observed that cancer-derived p53s with a mutant (primary antibody 1620-/pAb240+) conformation localized in the cytoplasm to a greater extent and displayed increased susceptibility to ubiquitination than p53s with a more wild-type (primary antibody 1620+/pAb240-) conformation. The cytoplasmic localization of mutant p53s required the C-terminal NES and an intact ubiquitination pathway. Mutant p53 ubiquitination occurred at lysines in both the DNA-binding domain (DBD) and C terminus. Interestingly, Lys to Arg mutations that inhibited ubiquitination restored nuclear localization to mutant p53 but had no apparent effect on p53 conformation. Further studies revealed that wild-type p53, like mutant p53, is ubiquitinated by MDM2 in both the DBD and C terminus and that ubiquitination in both regions contributes to its nuclear export. MDM2 binding can induce a conformational change in wild-type p53, but this conformational change is insufficient to promote p53 nuclear export in the absence of MDM2 ubiquitination activity. Taken together, these results support a stepwise model for mutant and wild-type p53 nuclear export. In this model, the conformational change induced by either the cancer-derived mutation or MDM2 binding precedes p53 ubiquitination. The addition of ubiquitin to DBD and C-terminal lysines then promotes nuclear export via the C-terminal NES.
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PMID:Regulation of p53 nuclear export through sequential changes in conformation and ubiquitination. 1737 68

The present study was designed to detect changes in p53 and MDM2 protein expression patterns in plasma from lung cancer patients. The largest p53 protein expression was observed in adenocarcinoma patients; however, mutant p53 was not increased in any cancer sample. A significant increase in the 57-kDa MDM2 isoform was observed in adenocarcinoma patients with low protein expression of the 90-kDa isoform. Our findings suggest that p53 accumulation could be due to a decrease in full-length MDM2 isoform together with an increase of the 57-kDa MDM2 isoform that was unable to stimulate p53 degradation.
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PMID:P53 and MDM2 isoforms in blood from lung cancer patients. 1762 Jan 86

Inactivation of p53-mediated signaling plays a major role in both the genesis and therapy resistance of human cancer. Nearly all tumors contain mutations in p53 itself or have perturbations in the p53 pathway. Since there is clear evidence that many tumor cells are more likely to die in response to wild-type p53 activation or restoration than are their normal counterparts, there has been considerable interest in the development of small molecules that target p53 for therapeutic gain. These include compounds that either revert mutant p53 back to its wild-type conformation or compounds which interfere with the binding to, or the ubiquitylation of, p53 by MDM2. In both cases, however, the efficacy of the strategy depends on the presence of either mutant or wild-type p53 respectively thereby limiting their application to specific tumor settings. As a result, recent strategies have turned to the p53 family member, p73, which like p53 is a potent inducer of death, but in contrast is rarely lost or mutated in tumors. We discuss here all these different strategies and in particular focus on the discovery of an apoptotic peptide which targets not just p73, but potentially all p53 family members to cause tumor cell death.
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PMID:Targeting the p53 family for cancer therapy: 'big brother' joins the fight. 1772 Oct 76

MDM2 is an oncoprotein best characterized for its role in the inactivation and degradation of the p53 tumor suppressor. However, MDM2 has many other binding partners and its p53-independent role in the regulation of cell growth and survival appears to be extremely complex. This report describes the expression of MDM2 in two rhabdomyosarcoma cell lines, both expressing a mutant p53 gene. Expression of MDM2 in Rh30 cells enhanced cell growth whereas expression of MDM2 in RD cells suppressed their growth and enhanced the rate of spontaneous apoptosis. The mechanism for these opposite phenotypes was demonstrated to be due to differential effects on the NFkappaB pathway. Previously MDM2 has been shown to activate NFkappaB through activation of transcription of the p65RelA subunit. In Rh30 cells MDM2 acted similarly to previously described, thereby promoting growth of Rh30 cells. In untreated RD cells p65RelA was constitutively overexpressed resulting in activation of the NFkappaB pathway. Expression of MDM2 in RD cells transcriptionally repressed p65RelA and suppressed NFkappaB activity, resulting in a reduced growth rate and enhanced apoptosis. The MDM2-sensitive region of the p65 promoter was localized to a 225 bp fragment to which MDM2 protein was shown to bind. The observation that MDM2 induces apoptosis under certain circumstances may help to explain the apparently surprising clinical studies that have shown that MDM2 expression in tumors is often associated with a favorable prognosis.
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PMID:MDM2 displays differential activities dependent upon the activation status of NFkappaB. 1793 75

In chronic lymphocytic leukaemia (CLL), mutation/deletion of TP53 is strongly associated with early disease progression, resistance to chemotherapy and short patient survival. Consequently, there is a pressing need to develop novel treatment protocols for this high-risk patient group. The present study was performed to evaluate Hsp90 inhibition as a possible therapeutic approach for such patients. Primary CLL cells of defined ataxia telangiectasia mutated (ATM)/p53 status were incubated with the Hsp90 inhibitor geldanamycin (GA) and analysed by western blotting for the expression of p53, p21, MDM2 and Akt. GA downregulated overexpressed mutant p53 protein (an oncogene) and upregulated wild-type (wt) p53 (a tumour suppressor). The upregulation of wt p53 by GA was independent of ATM and was accompanied by downregulation of Akt and the active form of MDM2, indicating a possible mechanism. GA also produced a p53/ATM-independent increase in the levels of p21-a potent inducer of cell-cycle arrest. In-vitro cytotoxicity studies showed that GA killed cultured CLL cells in a dose- and time-dependent fashion irrespective of their p53/ATM status and more effectively than normal blood mononuclear cells. In summary, our findings reveal important consequences of inhibiting Hsp90 in CLL cells and strongly support the therapeutic evaluation of Hsp90 inhibitors in poor-prognosis patients with p53 defects.
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PMID:Hsp90 inhibition has opposing effects on wild-type and mutant p53 and induces p21 expression and cytotoxicity irrespective of p53/ATM status in chronic lymphocytic leukaemia cells. 1798 89

p53 missense mutant proteins commonly show increased stability compared to wild-type p53, which is thought to depend largely on the inability of mutant p53 to induce the ubiquitin ligase MDM2. However, recent work using mouse models has shown that the accumulation of mutant p53 occurs only in tumour cells, indicating that stabilization requires additional factors. To clarify the stabilization of p53 mutants in tumours, we analysed factors that affect their folding and degradation. Although all missense mutants that we studied are more stable than wild-type p53, the levels correlate with individual structural characteristics, which may be reflected in different gain-of-function properties. In the absence of Hsp90 activity, the less stable unfolded p53 mutants preferentially associate in a complex with Hsp70 and CHIP (carboxy terminus of Hsp70-interacting protein), and we show that CHIP is responsible for ubiquitination and degradation of these mutants. The demonstration of a complex interplay between Hsp90, Hsp70 and CHIP that regulate the stability of different p53 mutant proteins improves our understanding of the pro-tumorigenic effects of increased Hsp90 activity during multi-stage carcinogenesis. Understanding the roles of Hsp90, Hsp70 and CHIP in cancers may also provide an important avenue through which to target p53 to enhance treatment of human cancers.
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PMID:Chaperone-dependent stabilization and degradation of p53 mutants. 1822 94

Sequence-specific binding by the human p53 master regulator is critical to its tumor suppressor activity in response to environmental stresses. p53 binds as a tetramer to two decameric half-sites separated by 0-13 nucleotides (nt), originally defined by the consensus RRRCWWGYYY (n = 0-13) RRRCWWGYYY. To better understand the role of sequence, organization, and level of p53 on transactivation at target response elements (REs) by wild type (WT) and mutant p53, we deconstructed the functional p53 canonical consensus sequence using budding yeast and human cell systems. Contrary to early reports on binding in vitro, small increases in distance between decamer half-sites greatly reduces p53 transactivation, as demonstrated for the natural TIGER RE. This was confirmed with human cell extracts using a newly developed, semi-in vitro microsphere binding assay. These results contrast with the synergistic increase in transactivation from a pair of weak, full-site REs in the MDM2 promoter that are separated by an evolutionary conserved 17 bp spacer. Surprisingly, there can be substantial transactivation at noncanonical (1/2)-(a single decamer) and (3/4)-sites, some of which were originally classified as biologically relevant canonical consensus sequences including PIDD and Apaf-1. p53 family members p63 and p73 yielded similar results. Efficient transactivation from noncanonical elements requires tetrameric p53, and the presence of the carboxy terminal, non-specific DNA binding domain enhanced transactivation from noncanonical sequences. Our findings demonstrate that RE sequence, organization, and level of p53 can strongly impact p53-mediated transactivation, thereby changing the view of what constitutes a functional p53 target. Importantly, inclusion of (1/2)- and (3/4)-site REs greatly expands the p53 master regulatory network.
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PMID:Noncanonical DNA motifs as transactivation targets by wild type and mutant p53. 1871 71

p53 missense mutations observed in human cancers are often associated with an increased level of p53 protein in the tumour. Using mouse models, Terzian et al. recently showed that this accumulation of mutant p53 protein is not associated with specific properties of the protein itself but instead depends on the endogenous genetic background of the tumours and on two important genes, mouse double minute 2 (Mdm2) and the cyclin kinase inhibitor p16INK4a. Mice expressing mutant p53 in the absence of Mdm2 display more aggressive metastatic tumours. In light of these observations, targeting the MDM2-p53 interaction for therapy of human cancer could be more complicated than previously anticipated.
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PMID:When mutant p53 plays hide and seek: a new challenge for diagnosis and therapy? 1909 39

The tumour suppressor p53 is known to prevent cancer progression by inhibiting proliferation and inducing apoptosis of tumour cells. Slug, an invasion promoter, exerts its effects by repressing E-cadherin transcription. Here we show that wild-type p53 (wtp53) suppresses cancer invasion by inducing Slug degradation, whereas mutant p53 may stabilize Slug protein. In non-small-cell lung cancer (NSCLC), mutation of p53 correlates with low MDM2, high Slug and low E-cadherin expression. This expression profile is associated with poor overall survival and short metastasis-free survival in patients with NSCLC. wtp53 upregulates MDM2 and forms a wtp53-MDM2-Slug complex that facilitates MDM2-mediated Slug degradation. Downregulation of Slug by wtp53 or MDM2 enhances E-cadherin expression and represses cancer cell invasiveness. In contrast, mutant p53 inactivates Slug degradation and leads to Slug accumulation and increased cancer cell invasiveness. Our findings indicate that wtp53 and p53 mutants may differentially control cancer invasion and metastasis through the p53-MDM2-Slug pathway.
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PMID:p53 controls cancer cell invasion by inducing the MDM2-mediated degradation of Slug. 1944 27


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